Our long-term goal is to advance the knowledge of the neurobiological and molecular mechanisms underlying chronic pain in sickle cell disease (SCD) and develop effective pharmacologic treatments. Pain is not only a life-long companion but also a predictor of mortality for the 100,000 Americans living with SCD, people mainly of African or Latin descent.1-3 Pain and SCD are so intimately intertwined, that African tribal words for the disease, spoken hundreds of years before Herrick described SCD in the western literature, are onomatopoeic for pain. Though it is now appreciated that SCD pain is characterized by chronic pain with episodes of acute pain,4-5 the neurobiology of chronic pain is poorly studied, not well characterized, and is refractory to currently available therapies,6-7 a century after Herrick's seminal paper.8 A great deal of research has been carried on the disease itself.9-10 Several transgenic models of SCD have been developed, including the humanized Berkeley (BERK)11 and Townes' sickle cell transgenic mice (TOW),12 both representing SCD phenotypes that closely mimics many features of severe SCD in humans.13-20 We propose to employ these well-characterized sickle cell transgenic mouse models for studying molecular and epigenetic mechanisms underlying chronic pain, which can hold much promise for a more thorough understanding of pain mechanisms in SCD and may guide development of effective therapies. This R35 program will advance the knowledge of molecular mechanisms underlying chronic pain in SCD and apply new knowledge to design and examine experimental therapeutics in mouse models of SCD. The program is designed to have flexibility that expanded or new research directions can be rapidly taken when new findings or emerging technology become available. Our research applies the power of molecular and cellular biology, pharmacology, neurobiology, epigenetics, targeted delivery, and other cutting-edge tools and we have existing research, expertise and research facility for studying sickle pain problem at molecular, cellular, and systems levels. This program will methodologically investigate chronic pain in SCD using several newly developed innovations and start to fill the void in our understanding of chronic pain of SCD. Having identified the CaMKII? target for SC pain and recently moved a CaMKII? inhibitor from bench to a Phase I study in patients with SCD, our team is uniquely suited to carry out research in this R35 program. Our innovation has a high probability of success given our outstanding track record, vibrant ongoing research program, and the designed flexibility in pursuing new research directions.